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Transgenic Expression of Insulin Receptor Substrate 2 in Murine B Cells Alters the Cell Density-Dependence of IgE Production In Vitro and Enhances IgE Production In Vivo¹

Ann E. Kelly-Welch^*, Helen Y. Wang^*, Ling-Mei Wang, Jacalyn H. Pierce, Gilbert Jay^*, Fred Finkelman and Achsah D. Keegan^2,*

^* Department of Immunology, Jerome Holland Laboratories, American Red Cross, Rockville, MD 20855; Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892; and University of Cincinnati, Children’s Research Hospital, Cincinnati, OH 45267

Previous studies have shown that insulin receptor substrate (IRS)1 and IRS2 mediate proliferative and antiapoptotic signaling through the IL-4R in 32D cells; however their role in regulating normal B cell responses is not clear. To investigate the role of IRS2 in normal B cell function, we developed IRS2 transgenic (Tg) mice on the C57BL/6 background. Western blot analysis revealed a 2-fold elevation in IRS2 protein levels in Tg⁺ mice compared with littermate controls and a 3-fold increase in basal tyrosine phosphorylated IRS2 in the absence of IL-4 stimulation. IL-4-induced tyrosine phosphorylation of IRS2 was elevated in Tg⁺ B cells, whereas IL-4-induced phosphorylation of STAT6 was similar between Tg⁺ and Tg^- B cells. Tg expression of IRS2 had little effect on IL-4-mediated proliferation and no effect on protection from apoptosis. However, production of IgE and IgG1 by Tg⁺ B cells using standard in vitro conditions was diminished 50–60%. Because Ig production in vitro is known to be highly cell concentration-dependent, we performed experiments at different cell concentrations. Interestingly, at very low B cell concentrations (1000–5000 B cells/well), IgE and IgG1 production by Tg⁺ B cells was greater than that of controls, whereas at higher cell concentrations (10,000–20,000 cells/well) Ig production by Tg⁺ B cells was less than controls. Furthermore, in vivo immunization with OVA-alum or goat anti-IgD resulted in elevated serum IgE levels in the Tg⁺ mice. These results indicate that overexpression of IRS2 alters the B cell intrinsic density-dependence of IgE and IgG1 production in vitro and enhances IgE responses in vivo.

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